tbuckley/cabot-search huggingface dataset:
A systematic review of 454 randomized controlled trials using the Dermatology Life Quality Index: experience in 69 diseases and 43 countries
Authors: Jui Vyas, Jeffrey R Johns, Faraz M Ali, Ravinder K Singh, John R Ingram, Sam Salek, Andrew Y Finlay
Journal: British Journal of Dermatology (2023)

Abstract Background Over 29 years of clinical application, the Dermatology Life Quality Index (DLQI) has remained the most used patient-reported outcome (PRO) in dermatology due to its robustness, simplicity and ease of use. Objectives To generate further evidence of the DLQI's utility in randomized controlled trials (RCTs) and to cover all diseases and interventions. Methods The methodology followed PRISMA guidelines and included seven bibliographical databases, searching articles published from 1 January 1994 until 16 November 2021. Articles were reviewed independently by two assessors, and an adjudicator resolved any opinion differences. Results Of 3220 screened publications, 454 articles meeting the eligibility criteria for inclusion, describing research on 198 190 patients, were analysed. DLQI scores were primary endpoints in 24 (5.3%) of studies. Most studies were of psoriasis (54.1%), although 69 different diseases were studied. Most study drugs were systemic (85.1%), with biologics comprising 55.9% of all pharmacological interventions. Topical treatments comprised 17.0% of total pharmacological interventions. Nonpharmacological interventions, mainly laser therapy and ultraviolet radiation treatment, comprised 12.2% of the total number of interventions. The majority of studies (63.7%) were multicentric, with trials conducted in at least 42 different countries; 40.2% were conducted in multiple countries. The minimal clinically importance difference (MCID) was reported in the analysis of 15.0% of studies, but only 1.3% considered full score meaning banding of the DLQI. Forty-seven (10.4%) of the studies investigated statistical correlation of the DLQI with clinical severity assessment or other PRO/quality of life tools; and 61–86% of studies had within-group scores differences greater than the MCID in ‘active treatment arms’. The Jadad risk-of-bias scale showed that bias was generally low, as 91.8% of the studies had Jadad scores of ≥ 3; only 0.4% of studies showed a high risk of bias from randomization. Thirteen per cent had a high risk of bias from blinding and 10.1% had a high risk of bias from unknown outcomes of all participants in the studies. In 18.5% of the studies the authors declared that they followed an intention-to-treat protocol; imputation for missing DLQI data was used in 34.4% of studies. Conclusions This systematic review provides a wealth of evidence of the use of the DLQI in clinical trials to inform researchers’ and ­clinicians’ decisions for its further use. Recommendations are also made for improving the reporting of data from future RCTs using the DLQI.
Targeting a mitochondrial E3 ubiquitin ligase complex to overcome AML cell-intrinsic Venetoclax resistance
Authors: Fumihiko Nakao, Kiyoko Setoguchi, Yuichiro Semba, Takuji Yamauchi, Jumpei Nogami, Kensuke Sasaki, Hiroshi Imanaga, Tatsuya Terasaki, Manaka Miyazaki, Shigeki Hirabayashi, Kohta Miyawaki, Yoshikane Kikushige, Takeshi Masuda, Koichi Akashi, Takahiro Maeda
Journal: Leukemia (2023)
Recent progress and structural analyses of domain‐selective BET inhibitors
Authors: Anand Divakaran, Daniel A. Harki, William C. K. Pomerantz
Journal: Medicinal Research Reviews (2023)

Abstract Epigenetic mechanisms for controlling gene expression through heritable modifications to DNA, RNA, and proteins, are essential processes in maintaining cellular homeostasis. As a result of their central role in human diseases, the proteins responsible for adding, removing, or recognizing epigenetic modifications have emerged as viable drug targets. In the case of lysine‐ε‐N‐acetylation (K ac ), bromodomains serve as recognition modules (“readers”) of this activating epigenetic mark and competition of the bromodomain‐K ac interaction with small‐molecule inhibitors is an attractive strategy to control aberrant bromodomain‐mediated gene expression. The bromodomain and extra‐terminal (BET) family proteins contain eight similar bromodomains. These BET bromodomains are among the more commonly studied bromodomain classes with numerous pan‐BET inhibitors showing promising anticancer and anti‐inflammatory efficacy. However, these results have yet to translate into Food and Drug Administration‐approved drugs, in part due to a high degree of on‐target toxicities associated with pan‐BET inhibition. Improved selectivity within the BET‐family has been proposed to alleviate these concerns. In this review, we analyze the reported BET‐domain selective inhibitors from a structural perspective. We highlight three essential characteristics of the reported molecules in generating domain selectivity, binding affinity, and mimicking K ac molecular recognition. In several cases, we provide insight into the design of molecules with improved specificity for individual BET‐bromodomains. This review provides a perspective on the current state of the field as this exciting class of inhibitors continue to be evaluated in the clinic.
Response to the Comments from the Groupe Francophone de Cytogénétique Hématologique (GFCH) on the 5th edition of the World Health Organization classification of haematolymphoid tumors
Authors: Reiner Siebert, Anna Schuh, German Ott, Ian A. Cree, Ming-Qing Du, Judith Ferry, Andreas Hochhaus, Kikkeri N. Naresh, Eric Solary, Joseph D. Khoury
Journal: Leukemia (2023)
Metabolic reprogramming in cancer: Mechanisms and therapeutics
Authors: Shiqi Nong, Xiaoyue Han, Yu Xiang, Yuran Qian, Yuhao Wei, Tingyue Zhang, Keyue Tian, Kai Shen, Jing Yang, Xuelei Ma
Journal: MedComm (2023)

Abstract Cancer cells characterized by uncontrolled growth and proliferation require altered metabolic processes to maintain this characteristic. Metabolic reprogramming is a process mediated by various factors, including oncogenes, tumor suppressor genes, changes in growth factors, and tumor–host cell interactions, which help to meet the needs of cancer cell anabolism and promote tumor development. Metabolic reprogramming in tumor cells is dynamically variable, depending on the tumor type and microenvironment, and reprogramming involves multiple metabolic pathways. These metabolic pathways have complex mechanisms and involve the coordination of various signaling molecules, proteins, and enzymes, which increases the resistance of tumor cells to traditional antitumor therapies. With the development of cancer therapies, metabolic reprogramming has been recognized as a new therapeutic target for metabolic changes in tumor cells. Therefore, understanding how multiple metabolic pathways in cancer cells change can provide a reference for the development of new therapies for tumor treatment. Here, we systemically reviewed the metabolic changes and their alteration factors, together with the current tumor regulation treatments and other possible treatments that are still under investigation. Continuous efforts are needed to further explore the mechanism of cancer metabolism reprogramming and corresponding metabolic treatments.
In Situ Formed ROS‐Responsive Hydrogel with STING Agonist and Gemcitabine to Intensify Immunotherapy against Pancreatic Ductal Adenocarcinoma
Authors: Meng Wang, Qida Hu, Junming Huang, Fu Zhang, Zhuo Yao, Shiyi Shao, Xinyu Zhao, Tingbo Liang
Journal: Advanced Healthcare Materials (2023)

Immunotherapy, the most revolutionary anticancer strategy, faces major obstacles in yielding desirable outcomes in pancreatic ductal adenocarcinoma (PDAC) due to the highly immunosuppressive tumor microenvironment (TME). Meanwhile, when used alone, the traditional first-line chemotherapeutic agent gemcitabine (GEM) in PDAC treatment is also insufficient to achieve lasting efficacy. In this study, a reactive oxygen species degradable hydrogel system, denoted as GEM-STING@Gel, is engineered to codeliver gemcitabine and the stimulator of interferon genes (STING) agonist DMXAA (5,6-dimethylxanthenone-4-acetic acid) into the tumor site. In this work, the strategy addresses the major challenges of current immunotherapies with a facile platform, which can synergistically activate innate immunity and promote the cytotoxic T lymphocytes infiltration at the tumor site, thereby modulating the immunosuppressive TME. Further, the efficient therapeutic potency of the immunotherapy is confirmed in an orthotopic postsurgical model, unleashing the translational potential to prevent tumor recurrence after surgical resection. This study underscores the advantages of this integrative strategy that combines chemotherapy, immunotherapy, and biomaterial-based hydrogel, including improved therapeutic efficacy, operational convenience, and superior biosafety.
Effectiveness of artificial intelligence screening in preventing vision loss from diabetes: a policy model
Authors: Roomasa Channa, Risa M. Wolf, Michael D. Abràmoff, Harold P. Lehmann
Journal: npj Digital Medicine (2023)

Abstract The effectiveness of using artificial intelligence (AI) systems to perform diabetic retinal exams (‘screening’) on preventing vision loss is not known. We designed the Care Process for Preventing Vision Loss from Diabetes (CAREVL), as a Markov model to compare the effectiveness of point-of-care autonomous AI-based screening with in-office clinical exam by an eye care provider (ECP), on preventing vision loss among patients with diabetes. The estimated incidence of vision loss at 5 years was 1535 per 100,000 in the AI-screened group compared to 1625 per 100,000 in the ECP group, leading to a modelled risk difference of 90 per 100,000. The base-case CAREVL model estimated that an autonomous AI-based screening strategy would result in 27,000 fewer Americans with vision loss at 5 years compared with ECP. Vision loss at 5 years remained lower in the AI-screened group compared to the ECP group, in a wide range of parameters including optimistic estimates biased toward ECP. Real-world modifiable factors associated with processes of care could further increase its effectiveness. Of these factors, increased adherence with treatment was estimated to have the greatest impact.
Severe Infection and Risk of Cardiovascular Disease: A Multicohort Study
Authors: Pyry N. Sipilä, Joni V. Lindbohm, G. David Batty, Nelli Heikkilä, Jussi Vahtera, Sakari Suominen, Ari Väänänen, Aki Koskinen, Solja T. Nyberg, Seppo Meri, Jaana Pentti, Charlotte Warren-Gash, Andrew C. Hayward, Mika Kivimäki
Journal: Circulation (2023)

The excess risk of cardiovascular disease associated with a wide array of infectious diseases is unknown. We quantified the short- and long-term risk of major cardiovascular events in people with severe infection and estimated the population-attributable fraction. We analyzed data from 331 683 UK Biobank participants without cardiovascular disease at baseline (2006-2010) and replicated our main findings in an independent population from 3 prospective cohort studies comprising 271 329 community-dwelling participants from Finland (baseline 1986-2005). Cardiovascular risk factors were measured at baseline. We diagnosed infectious diseases (the exposure) and incident major cardiovascular events after infections, defined as myocardial infarction, cardiac death, or fatal or nonfatal stroke (the outcome) from linkage of participants to hospital and death registers. We computed adjusted hazard ratios (HRs) and 95% CIs for infectious diseases as short- and long-term risk factors for incident major cardiovascular events. We also calculated population-attributable fractions for long-term risk. In the UK Biobank (mean follow-up, 11.6 years), 54 434 participants were hospitalized for an infection, and 11 649 had an incident major cardiovascular event at follow-up. Relative to participants with no record of infectious disease, those who were hospitalized experienced increased risk of major cardiovascular events, largely irrespective of the type of infection. This association was strongest during the first month after infection (HR, 7.87 [95% CI, 6.36-9.73]), but remained elevated during the entire follow-up (HR, 1.47 [95% CI, 1.40-1.54]). The findings were similar in the replication cohort (HR, 7.64 [95% CI, 5.82-10.03] during the first month; HR, 1.41 [95% CI, 1.34-1.48] during mean follow-up of 19.2 years). After controlling for traditional cardiovascular risk factors, the population-attributable fraction for severe infections and major cardiovascular events was 4.4% in the UK Biobank and 6.1% in the replication cohort. Infections severe enough to require hospital treatment were associated with increased risks for major cardiovascular disease events immediately after hospitalization. A small excess risk was also observed in the long-term, but residual confounding cannot be excluded.
A T follicular helper cell origin for T regulatory type 1 cells
Authors: Patricia Solé, Jun Yamanouchi, Josep Garnica, Muhammad Myn Uddin, Robert Clarke, Joel Moro, Nahir Garabatos, Shari Thiessen, Mireia Ortega, Santiswarup Singha, Debajyoti Mondal, César Fandos, Julio Saez-Rodriguez, Yang Yang, Pau Serra, Pere Santamaria
Journal: Cellular and Molecular Immunology (2023)

Abstract Chronic antigenic stimulation can trigger the differentiation of antigen-experienced CD4 + T cells into T regulatory type 1 (TR1) cells, a subset of interleukin-10-producing Treg cells that do not express FOXP3. The identities of the progenitor(s) and transcriptional regulators of this T-cell subset remain unclear. Here, we show that the peptide-major histocompatibility complex class II (pMHCII) monospecific immunoregulatory T-cell pools that arise in vivo in different genetic backgrounds in response to pMHCII-coated nanoparticles (pMHCII-NPs) are invariably comprised of oligoclonal subpools of T follicular helper (TFH) and TR1 cells with a nearly identical clonotypic composition but different functional properties and transcription factor expression profiles. Pseudotime analyses of scRNAseq data and multidimensional mass cytometry revealed progressive downregulation and upregulation of TFH and TR1 markers, respectively. Furthermore, pMHCII-NPs trigger cognate TR1 cell formation in TFH cell-transfused immunodeficient hosts, and T-cell-specific deletion of Bcl6 or Irf4 blunts both the TFH expansion and TR1 formation induced by pMHCII-NPs. In contrast, deletion of Prdm1 selectively abrogates the TFH-to-TR1 conversion. Bcl6 and Prdm1 are also necessary for anti-CD3 mAb-induced TR1 formation. Thus, TFH cells can differentiate into TR1 cells in vivo, and BLIMP1 is a gatekeeper of this cellular reprogramming event.
A phase <scp>II</scp> study of sintilimab, anlotinib, and pegaspargase sandwiched with radiotherapy as first‐line therapy in patients with newly diagnosed, stage <scp>I–II</scp> extranodal natural‐killer/T‐cell lymphoma
Authors: Peng Sun, Yajun Li, Cong Li, Kexing Ren, Yu Wang, Hang Yang, Wenqi Jiang, Liqun Zou, Haiyan Yang, Hui Zhou, Zhi‐Ming Li
Journal: American Journal of Hematology (2023)

Abstract Novel highly effective and low‐toxicity combination therapy for localized extranodal natural‐killer/T‐cell lymphoma (ENKTL) remains a clinically unmet need. This phase II trial (NCT03936452) investigated the efficacy and safety of sintilimab, anlotinib, and pegaspargase sandwiched with radiotherapy as first‐line treatment in patients with newly‐diagnosed stage I–II ENKTL. The patients received sintilimab 200 mg plus pegaspargase 2500 U/m 2 on day 1 and anlotinib 12 mg once daily on days 1–14 for three 21‐day cycles, followed by intensity‐modulated radiotherapy and another three cycles of systemic therapy. The primary endpoint was the complete response rate (CRR) after six treatment cycles. The secondary endpoints included progression‐free survival (PFS), overall survival (OS), CRR after two cycles, overall response rate (ORR) after six cycles, duration of response (DOR), and safety. Between May 2019 and July 2021, 58 patients were enrolled. The CRR was 55.1% (27/49) after two cycles and 87.8% (43/49) after six cycles. The ORR was 87.8% (43/49; 95% CI, 75.2–95.4) after six cycles. After a median follow‐up of 22.5 months (95% CI, 20.4–24.6), the median PFS, OS, and DOR were not reached. The 2‐year PFS, OS, and DOR rates were 87.6% (95% CI, 78.8–97.4), 97.9% (95% CI, 94.0–100), and 91.1% (95% CI, 83.2–99.8), respectively. Grade 3–4 treatment‐related adverse events occurred in 41.4% (24/58) of patients, with the most common being hypertension (15.5%), hypertriglyceridemia (8.6%), oral mucositis (6.9%), and anemia (5.2%). No treatment‐related deaths occurred. First‐line sintilimab, anlotinib, and pegaspargase sandwiched with radiotherapy demonstrated promising efficacy in treatment‐naïve early‐stage ENKTL patients with a favorable safety profile.
Impaired Reorganization of Centrosome Structure Underlies Human Infantile Dilated Cardiomyopathy
Authors: Young Wook Chun, Matthew Miyamoto, Charles H. Williams, Leif R. Neitzel, Maya Silver-Isenstadt, Adrian G. Cadar, Daniela T. Fuller, Daniel C. Fong, Hanhan Liu, Robert Lease, Sungseek Kim, Mikako Katagiri, Matthew D. Durbin, Kuo-Chen Wang, Tromondae K. Feaster, Calvin C. Sheng, M. Diana Neely, Urmila Sreenivasan, Marcia Cortes-Gutierrez, Aloke V. Finn, Rachel Schot, Grazia M.S. Mancini, Seth A. Ament, Kevin C. Ess, Aaron B. Bowman, Zhe Han, David P. Bichell, Yan Ru Su, Charles C. Hong
Journal: Circulation (2023)

During cardiomyocyte maturation, the centrosome, which functions as a microtubule organizing center in cardiomyocytes, undergoes dramatic structural reorganization where its components reorganize from being localized at the centriole to the nuclear envelope. This developmentally programmed process, referred to as centrosome reduction, has been previously associated with cell cycle exit. However, understanding of how this process influences cardiomyocyte cell biology, and whether its disruption results in human cardiac disease, remains unknown. We studied this phenomenon in an infant with a rare case of infantile dilated cardiomyopathy (iDCM) who presented with left ventricular ejection fraction of 18% and disrupted sarcomere and mitochondria structure.
Engineering Modular, Oxygen‐Generating Microbeads for the In Situ Mitigation of Cellular Hypoxia
Authors: Robert P. Accolla, Jia‐Pu Liang, Taylor R. Lansberry, Irayme Labrada Miravet, Marlon Loaisiga, Baltasar Lopez Sardi, Cherie L. Stabler
Journal: Advanced Healthcare Materials (2023)

Insufficient oxygenation is a key obstacle in the design of clinically scalable tissue-engineered grafts. In this work, an oxygen-generating composite material, termed OxySite, is created through the encapsulation of calcium peroxide (CaO
Tailored Beta‐Lapachone Nanomedicines for Cancer‐Specific Therapy
Authors: Yaru Li, Meiyu Feng, Tao Guo, Zheng Wang, Yanjun Zhao
Journal: Advanced Healthcare Materials (2023)

Abstract Nanotechnology shows the power to improve efficacy and reduce the adverse effects of anticancer agents. As a quinone‐containing compound, beta‐lapachone (LAP) is widely employed for targeted anticancer therapy under hypoxia. The principal mechanism of LAP‐mediated cytotoxicity is believed due to the continuous generation of reactive oxygen species with the aid of NAD(P)H: quinone oxidoreductase 1 (NQO1). The cancer selectivity of LAP relies on the difference between NQO1 expression in tumors and that in healthy organs. Despite this, the clinical translation of LAP faces the problem of narrow therapeutic window that is challenging for dose regimen design. Herein, the multifaceted anticancer mechanism of LAP is briefly introduced, the advance of nanocarriers for LAP delivery is reviewed, and the combinational delivery approaches to enhance LAP potency in recent years are summarized. The mechanisms by which nanosystems boost LAP efficacy, including tumor targeting, cellular uptake enhancement, controlled cargo release, enhanced Fenton or Fenton‐like reaction, and multidrug synergism, are also presented. The problems of LAP anticancer nanomedicines and the prospective solutions are discussed. The current review may help to unlock the potential of cancer‐specific LAP therapy and speed up its clinical translation.
Immunomodulatory properties of mesenchymal stem cells/dental stem cells and their therapeutic applications
Authors: Peishan Li, Qianmin Ou, Songtao Shi, Changshun Shao
Journal: Cellular and Molecular Immunology (2023)

Abstract Mesenchymal stem/stromal cells (MSCs) are widely distributed in the body and play essential roles in tissue regeneration and homeostasis. MSCs can be isolated from discarded tissues, expanded in vitro and used as therapeutics for autoimmune diseases and other chronic disorders. MSCs promote tissue regeneration and homeostasis by primarily acting on immune cells. At least six different types of MSCs have been isolated from postnatal dental tissues and have remarkable immunomodulatory properties. Dental stem cells (DSCs) have been demonstrated to have therapeutic effects on several systemic inflammatory diseases. Conversely, MSCs derived from nondental tissues such as the umbilical cord exhibit great benefits in the management of periodontitis in preclinical studies. Here, we discuss the main therapeutic uses of MSCs/DSCs, their mechanisms, extrinsic inflammatory cues and the intrinsic metabolic circuitries that govern the immunomodulatory functions of MSCs/DSCs. Increased understanding of the mechanisms underpinning the immunomodulatory functions of MSCs/DSCs is expected to aid in the development of more potent and precise MSC/DSC-based therapeutics.
Bimekizumab maintenance of response through 3 years in patients with moderate-to-severe plaque psoriasis: results from the BE BRIGHT open-label extension trial
Authors: Bruce Strober, Yayoi Tada, Ulrich Mrowietz, Mark Lebwohl, Peter Foley, Richard G Langley, Richard B Warren, Maggie Wang, Veerle Vanvoorden, Balint Szilagyi, Valerie Ciaravino, Carle Paul
Journal: British Journal of Dermatology (2023)

Given the chronic nature of psoriasis and the loss of response that can be observed with therapies over time, it is important to understand the long-term efficacy of new treatments.To evaluate maintenance of Week 16 responses with bimekizumab (BKZ) treatment through Year 3, in patients with moderate-to-severe plaque psoriasis.Data were pooled from BKZ-treated patients in the 52-week (BE VIVID) and 56-week (BE READY and BE SURE) phase III studies, and their ongoing open-label extension (OLE), BE BRIGHT. Efficacy outcomes are reported through 3 years of BKZ treatment in patients with an efficacy response at Week 16. Missing data were imputed primarily using modified nonresponder imputation (mNRI), with nonresponder imputation and observed case data also reported.A total of 989 patients were randomized to BKZ at baseline in BE VIVID, BE READY and BE SURE. At Week 16, 693 patients achieved ≥ 90% reduction from baseline in Psoriasis Area and Severity Index (PASI 90), 503 achieved 100% reduction from baseline in PASI (PASI 100), 694 achieved absolute PASI ≤ 2 and 597 achieved body surface area (BSA) ≤ 1%, and continued into the OLE. Of these, 93.0% maintained PASI 90, 80.8% maintained PASI 100, 94.0% maintained PASI ≤ 2 and 90.3% maintained BSA ≤ 1% responses through to 3 years of BKZ treatment (mNRI). Among Week 16 PASI 90 responders, 96.8% and 72.5% also achieved Investigator's Global Assessment 0/1 and PASI 100 at Week 16, respectively, and 92.2% and 73.4% achieved these responses at Year 3 (mNRI). Among Week 16 PASI 100 responders, 76.3% also achieved Dermatology Life Quality Index (DLQI) 0/1 at Week 16, and DLQI 0/1 response increased with continuous BKZ treatment to 89.0% at Year 3 (mNRI).High levels of clinical response were maintained through to 3 years of BKZ treatment in the vast majority of Week 16 responders. Long-term treatment with BKZ was efficacious, with important benefits for health-related quality of life, in patients with moderate-to-severe plaque psoriasis.